Cytotoxicity of 11-epi-sinulariolide acetate isolated from cultured soft corals on HA22T cells through the endoplasmic reticulum stress pathway and mitochondrial dysfunction

Jen Jie Lin, Robert Y.L. Wang, Jiing Chuan Chen, Chien Chih Chiu, Ming Hui Liao, Yu Jen Wu*

*Corresponding author for this work

Research output: Contribution to journalJournal Article peer-review

15 Scopus citations

Abstract

Natural compounds from soft corals have been increasingly used for their antitumor therapeutic properties. This study examined 11-epi-sinulariolide acetate (11-epi-SA), an active compound isolated from the cultured soft coral Sinularia flexibilis, to determine its potential antitumor effect on four hepatocellular carcinoma cell lines. Cell viability was investigated using 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, and the results demonstrated that 11-epi-SA treatment showed more cytotoxic effect toward HA22T cells. Protein profiling of the 11-epi-SA-treated HA22T cells revealed substantial protein alterations associated with stress responseand protein synthesis and folding, suggesting that the mitochondria and endoplasmic reticulum (ER) play roles in 11-epi-SA-initiated apoptosis. Moreover, 11-epi-SA activated caspase-dependent apoptotic cell death, suggesting that mitochondria-related apoptosis genes were involved in programmed cell death. The unfolded protein response signaling pathway-related proteins were also activated on 11-epi-SA treatment, and these changes were accompanied by the upregulatedexpression of growth arrest and DNA damage-inducible protein (GADD153) and CCAAT/enhancer bindingprotein (C/EBP) homologous protein (CHOP), the genes encoding transcription factors associated withgrowth arrest and apoptosis under prolonged ER stress. Two inhibitors, namely salubrinal (Sal) and SP600125, partially abrogated 11-epi-SA-related cell death, implying that the protein kinase R(PKR)-like endoplasmic reticulum kinase (PERK)-activating transcription factor (ATF) 6-CHOP or the inositol-requiring enzyme 1 alpha (IRE1α)-c-Jun N-terminal kinase (JNK)-cJun signal pathway was activated after 11-epi-SA treatment. In general, these results suggest that 11-epi-SA exerts cytotoxiceffects on HA22T cells through mitochondrial dysfunction and ER stress cell death pathways.

Original languageEnglish
Article number1787
JournalInternational Journal of Molecular Sciences
Volume17
Issue number11
DOIs
StatePublished - 11 2016

Bibliographical note

Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.

Keywords

  • 11-epi-sinulariolide acetate
  • Antitumor
  • ER stress
  • Hepatocellular carcinoma
  • Mitochondrial dysfunction

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